This invention relates to the use of tri(halo- or trifluoromethyl) substituted N-fluorotriazinium salts to fluorinate non-activated aromatic compounds (i.e. unsubstituted aromatic compounds and aromatic compounds having one or more electron-withdrawing substituents).
Fluorination is an important process in many areas of industry, in particular where the synthesis of specialty chemicals is concerned. Known fluorination methods are conveniently categorized according to the perceived manner in which the fluorinating agents provide fluorine for combination with an active site in an organic molecule, namely as fluorine atom (Fxe2x80xa2), fluoride ion (Fxe2x88x92) or, conceptually, fluoronium ion (F+). Fluorinations involving fluorine atom are notoriously exothermic and non-selective, hence xe2x80x9clightxe2x80x9d strategic fluorination of organic compounds (that is, the introduction of one or two fluorine substituents or a trifluoromethyl group at key molecular sites) rests on the availability of versatile ranges of nucleophilic and electrophilic sources of fluorine. Of late, the use of N-fluoro compounds has become one of the most widely used methods for the selective formation of carbon-fluorine bonds via xe2x80x9celectrophilicxe2x80x9d mechanisms. A recent comprehensive review of this synthetic methodology contains no reference to N-F reagents derived from triazines (see G. G. Furin in Methods of Organic Chemistry (Houben-Weyl): Volume E10a; Organofluorine Compounds (ed. B. Baasner, H. Hagemann, and J. C. Tatlow), Georg Thieme Verlag, Stuttgart, 1999, pp. 432-499.
1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (so-called F-TEDA-BF4) is a known, commercially available (under the trade name xe2x80x9cSelectfluorxe2x80x9d) fluorinating agent and is useful as a general purpose fluorinating agent. However this material has only a moderate fluorinating power and is able to fluorinate benzene only under forcing conditions, for example under reflux for 24 hours. The chemistry of F-TEDA-BF4 has been reviewed by R. E. Banks in J. Fluorine Chemistry 87 (1998) 1-17, the whole content of which is incorporated herein by reference.
N-Fluoropyridinium salts and ring-substituted analogues thereof, e.g. N-fluoropyridinium triflate, are known for use as a fluorinating agent but have relatively low fluorinating power. U.S. Pat. No. 4,828,764 discloses that certain N-fluoro-N-perfluoroalkyl or perfluoroaryl sulfonamides including, inter alia, those of the formula RfSO2NFR are electrophilic fluorinating agents. In this formula Rf represents a perfluorinated C1-C30 alkyl, C3-C30 cycloalkyl, C6-C14 aryl substituted C1-C10 alkyl or a C6-C14 aryl group and R represents a C1-C30 alkyl, C3-C30 cycloalkyl, C6-C14 aryl substituted C1-C10 alkyl, or C6-C14 aryl group optionally substituted with one or more inert substituents including, inter alia, fluorine and, when Rf is trifluoromethyl, R alternatively can represent perfluoromethyl-sulfonamido. The preferred fluorinating agents are stated to be N-fluorobis-(trifluoromethanesulfonyl)imide (Rfxe2x95x90CF3 and R=CF3SO2), known as DesMarteau""s Reagent, and N-fluoro-N-methyltrifluoromethanesulfonamide (Rfxe2x95x90CF3 and R=CH3). DesMarteau""s Reagent is a powerful electrophilic fluorinating agent which is capable of converting benzene to fluorobenzene at room temperature but is hazardous, time-consuming and expensive to prepare requiring eight or nine reaction steps from readily available material. Only a very limited number of other known fluorinating agents are strong enough to fluorinate benzene without forcing conditions but they often provide relatively low yields or require special precautions. Those reported to fluorinate benzene include, in addition to DesMarteau""s Reagent, CF3OF, XeF2, NF4+, BF4xe2x88x92, N2F+AsF6xe2x88x92, N-fluoropentachloropyridium triflate, perfluoro-[N-fluoro-N-(4-pyridyl)methanesulfonamide] and N-fluoro-2,6-bis(methoxycarbonyl)pyridinium triflate. Very few of these compounds, only NF4+ BF4xe2x88x92 and XeF2, are known to fluorinate aromatic substrates having electron-withdrawing substituents such as nitrobenzene.
N-Fluorotriazinium salts of the following Formula A are known: 
wherein:
(i) X=H and Yxe2x88x92=AsF6xe2x88x92 (Ref.1xe2x80x94see below)
(ii) X=F and Yxe2x88x92=AsF6xe2x88x92 (Ref. 2xe2x80x94see below)
(iii) X=F and Yxe2x88x92=BF4xe2x88x92 (Ref. 3xe2x80x94see below) and
(iv) X=Cl and Yxe2x88x92=AsF6xe2x88x92 (Refs. 2 and 4xe2x80x94see below).
The N-fluorotriazinium salts of Formula A are reported to be oxidizing agents of use in, for example, organometallic chemistry. The cationic component of compounds of Formula A in which X is H, F and Cl have been described as xe2x80x9coxidative fluorinatorsxe2x80x9d and a qualitative scale for their oxidizing strength and that of NF4+ has been computed ab initio (Ref. 3xe2x80x94see below).
Ref. 1=Broschag et al. Inorg. Chim. Acta, 205 (1993) 167-173;
Ref. 2=Schleyer et al. Inorg. Chem. 32 (1993) 1523-1524;
Ref. 3=Schulz and Klapxc3x6tke J. Organometal. Chem. 480 (1994) 195-197; and
Ref. 4=Broschag et al. Z. Anorg. Allg. Chem., 620 (1994) 1132-1136.
There is a statement in Schleyer et al. that 1-fluoro-2,4,6-trichloro-s-triazinium hexafluoroarsenate (Formula A; X=Cl; and Yxe2x88x92=AsF6xe2x88x92) xe2x80x9cis a promising fluorination agentxe2x80x9d but no further details were provided or subsequently reported. It is believed that uses of the compounds of Formula A other than as oxidizing agents was not contemplated or investigated. In particular, there is no disclosure in the prior art of any of these compounds being evaluated as oxidative fluorinators (as distinct from non-fluorinating oxidizing agents) despite the computed values reported in Refs. 3 and 4.
We have now surprisingly found that tri(halo- or trifluoromethyl) substituted N-fluorinated triazinium salts are sufficiently strong electrophilic fluorinating agents that they will readily fluorinate non-activated aromatic compounds. The N-fluorotriazinium salts can be represented by the following Formula I: 
in which:
three A moieties are independently CR, where each R is independently halogen or trifluoromethyl;
two A moieties are independently Z, where each Z is independently nitrogen or a quaternary nitrogen atom; and
Yxe2x88x92 is a counterion or group of counterions which are inert to chemical attack by fluorine.
In its broadest aspect, the present invention provides a method of fluorinating a substrate selected from the group consisting of unsubstituted aromatic compounds and aromatic compounds having one or more electron-withdrawing substituents which comprises contacting the substrate with a tri(halo- or trifluoromethyl) substituted N-fluorotriazinium salt.
The N-fluorotriazinium salts are of the following Formula I: 
wherein:
three A moieties are independently CR, where each R is independently halogen or trifluoromethyl;
two A moieties are independently Z, where each Z is independently nitrogen or a quaternary nitrogen atom; and
Yxe2x88x92 is a counterion or group of counterions which are inert to chemical attack by fluorine.
It is presently preferred that the triazinium compounds are 1,2,4-triazinium compounds of the following Formula IA or, especially, 1,3,5-triazinium compounds of the following Formula IB: 
wherein:
R1, R2 and R3are independently halogen or trifluoromethyl;
Z1 and Z2 are independently nitrogen or a quaternary nitrogen atom; and
Yxe2x88x92 is a counterion or group of counterions which are inert to chemical attack by fluorine.
As mentioned above, the N-fluoro-triazinium salts of Formula I are remarkably strong fluorinating agents capable of room temperature fluorination of unsubstituted aromatic substrates such as benzene and aromatic substrates having one or more electron-withdrawing substituents such as chlorobenzene or nitrobenzene.
Usually, all R substituents, or R1, R2 and R3 for Formulae IA and IB, are identical in a given compound.
The compounds of Formula I contain at least one fluorinated quaternary nitrogen atom in the triazinium ring and one or both of the other triazinium nitrogen atoms may be quaternary, preferably fluorinated, nitrogen. In a preferred embodiment both Z, or both Z1 and Z2 for Formulae IA and IB, are nitrogen and the most preferred compounds are those of the following Formula II: 
wherein R1, R2, R3 and Yxe2x88x92 are as defined above.
Examples of preferred compounds according to the invention are those having a triazinium cation as shown below in Formulae III to V. 
1-fluoro-2,4,6-tris(trifluoromethyl)-1,3,5-triazinium 
1-fluoro-2,4,6-trichloro-1,3,5-triazinium 
1-fluoro-2,4,6-trifluoro-1,3,5-triazinium
The counterion Yxe2x88x92 is resistant to chemical attack by fluorine and desirably, is thermally stable and possesses low environmental toxicity. The counterion(s) can be any anion(s) which can be counterion(s) to the triazinium cation. The counterion(s) may have a single charge or a multiple charge or be a group of counterions so as to balance the charge of the triazinium moiety. Also the counterion may be a counterion to more than one mole of the triazinium cation, for example where the cation has a single charge and the counterion has a multiple charge.
Suitably the counterion is weakly nucleophilic. Suitable anions include fluoride; fluorosulfate (SO3Fxe2x88x92); alkanesulfonate, especially methanesulfonate (CH3SO3xe2x88x92); alkyl sulfate, especially methyl sulfate (CH3SO4xe2x88x92); perfluoroalkanesulfonate, preferably triflate (CF3SO3xe2x88x92) and nonaflate (C4F9O3xe2x88x92); arenesulfonate, especially tosylate (i.e. p-toluenesulfonate; p-CH3C6H4SO3xe2x88x92); alkanecarboxylate; perfluoroalkanecarboxylate; tetrafluoroborate (BF4xe2x88x92); tetraphenylborate (Ph4Bxe2x88x92); hexafluorophosphate (PF6xe2x88x92); hexafluoroantimonate (SbF6xe2x88x92); hexafluoroarsenate (AsF6xe2x88x92); chlorate (ClO3xe2x88x92); sulfate (SO42xe2x88x92=2Yxe2x88x92); hydrogen sulfate (HSO4xe2x88x92) and F(HF)xxe2x88x92 where x is at least 1. Presently preferred counterions include fluoride, tetrafluoroborate, triflate, tosylate, hexafluoroarsenate and hexafluorophosphate.
Preferably, the compounds of Formula I are prepared using a solvent-based process which comprises contacting a triazine compound with a fluorine source under acidic conditions in a solvent which is inert under the process conditions.
Suitably the fluorine source is an electrophilic fluorine source such as, for example, fluorine gas or a mixture of fluorine gas and a neutral compound derivable from a fluorine-containing counterion Yxe2x88x92 by removing at least one fluoride ion from Yxe2x88x92, for example boron trifluoride. Preferably, the fluorine source is fluorine gas. While the fluorine gas may be used without dilution, in general, it is preferable to use fluorine gas diluted with an inert gas so that the volume of the inert gas is between about 99.9% and about 50% for controlling the vigorous reaction. Suitable inert gases include nitrogen, helium and argon.
The triazine compound to be fluorinated is suitably a compound of the Formula VI and may be obtained by subjecting a compound or a mixture of compounds of formula RCN to a known process for producing a triazine compound of formula (RCN)3, wherein R is independently R1, R2 or R3 as described herein: 
The fluorination process is carried out in the presence of an acid which may be a Brxc3x8nsted acid (organic or mineral) or a Lewis acid. The level of acid is suitably adjusted so as to reduce and desirably avoid double protonation of the triazine compound and to provide a yield (as determined by 19F NMR) of Fxe2x80x94N+ of at least about 20% and desirably of at least about 50%. Desirably the molar ratio of acid to triazine substrate is about 0.5 to about 2.5, preferably about 1 to about 2.2.
Preferable examples of Brxc3x8nsted acid have pKa in the range from about 12.4 to about 4.6 and include halogenated alcohols, for example chlorodifluoroethanol, dichlorofluoroethanol, chlorooctafluoro-t-butanol, trifluoroethanol, tetrafluoropropanol, pentafluoropropanol, hexafluoroisopropanol, octafluoropentanol, and nonafluoro-t-butanol. Fluorinated alcohols, particularly those which are free of chlorine, are especially preferred.
Other acids which are especially preferred include acids of the counterion Yxe2x88x92 described above, for example anhydrous hydrofluoric acid, hexafluoroantimonic acid, tetrafluoroboric acid and triflic acid, sulfuric acid, methanesulfonic acid, acetic acid and trifluoroacetic acid.
Brxc3x8nsted acids may be used in the form of a complex with ethers, water, alcohols, nitriles, carboxylic acids and the like and may be used in the form of an aqueous solution.
Preferably, the solvent is non-aqueous and it is presently particularly preferred that the solvent is acetonitrile, a halogenated, especially fluorinated, alcohol or, especially, nitromethane. In this connection, it is believed that there has not been any previous proposal to use nitromethane as a solvent, or for any other purpose, with any N-F or +N-F reagent.
If desired the same material may be used as both the acid and the solvent.
The reaction to produce a compound of Formula I is carried out at a temperature at which the solvent is in the liquid phase and suitably at a sufficiently low temperature that reaction due to a free radical mechanism is reduced and suitably avoided. The particular temperature selected depends on the solvent and also the reactants. By way of example only, the reaction suitably may be carried out at a temperature of about xe2x88x9240 to about 10xc2x0 C. A temperature of about xe2x88x9240 to about xe2x88x9220xc2x0 C. is preferred for acetonitrile and a temperature of about xe2x88x9210 to about 5xc2x0 C. is preferred for hexafluoroisopropyl alcohol. The reaction may be carried out at elevated pressure although this is not essential.
Fluorination of the triazine compound may be carried out using a stirred-tank batch reactor. Where the fluorine source is gaseous, the fluorine source is suitably admitted either as neat gas at sub-atmospheric pressure or as a continuous flow of fluorine blended with nitrogen or other inert diluent at about atmospheric pressure. Advantageously, the process for producing compound of Formula I may be operated as a continuous process.
The compounds of Formula I may be used as electrophilic fluorinating agents in a similar manner to Selecffluor(trademark) and in manner know in the art (see, for example, R. E. Banks et al. J. Chem. Soc. Perkin Trans. I, 1996, 2069). The fluorinating agent may be contacted with the substrate neat and optionally at elevated temperature. If desired the fluorination process may be carried out in a solvent, for example acetonitrile or, especially, nitromethane. As mentioned above, it is believed that there has not been any previous proposal to use nitromethane as a solvent, or for any other purpose, with any N-F or +N-F reagent.
When a compound of Formula I has been used in a fluorination reaction and so depleted in fluorine, it may be recovered and regenerated by introducing the fluorine source for reuse in further fluorination reactions.
Compounds of Formula I may be isolated or used without separation from the reaction mixture. If desired, the reaction mixture may be fed to a separate fluorination reactor or the compound of Formula I may be purified or otherwise treated prior to use.
Accordingly, the invention also provides a method of producing a fluorinated substrate which comprises contacting, preferably under acidic conditions, a tri(halo or trifluoromethyl)triazine compound with a fluorine source in a solvent, which is inert under the process conditions, such that at least one of the nitrogen atoms in the triazine compound is fluorinated to produce a compound of Formula I and contacting, in situ or subsequently, the compound with a substrate to be fluorinated.
The invention is illustrated by the following non-limiting Examples.